The Pépin Laboratory
The Pépin Laboratory in the Department of Surgery at Massachusetts General Hospital is exploring the basic biology of how hormones regulate female reproductive development with the goal of translating curiosity-driven research to the clinic to benefit Women’s health. In addition to sex steroids, the ovary produces a number of other less understood reproductive hormones such as the anti-Müllerian hormone (AMH, also known as Mullerian inhibiting substance, or MIS) and follistatin (FST), which are necessary for female health. While we continue to apply novel technologies to pursue all aspects of reproduction, contraception, oncofertility, reproductive aging, and oncology, our ultimate goal is to develop therapeutics capable of modulating the MIS and FST pathways and evaluate them in our fertility and ovarian cancer models to develop new treatments that address unmet clinical needs in women’s health and beyond.
Our Mission
Explore curiosity driven research in reproductive development, learn how eggs stay dormant, learn how the female reproductive tract is made, and learn how it goes wrong in cancer. Follow the science first, but keep the patients in our minds: treat infertility, develop new therapies for ovarian cancer, provide more contraceptive choices, improve Women’s health. And have fun doing it!
The Research
Contraception
Our goal is to develop a new class of hormonal contraceptives that act on primordial follicle activation, the initial step of ovarian follicular development. We have identified anti-Müllerian hormone (AMH) as an inhibitory hormone that can induce long-term contraception in mammals, and its receptor AMHR2 as a promising druggable therapeutic target for contraception (Kano et al., 2017).
These discoveries culminated with the development of gene therapy technologies to deliver a safe and effective alternative to surgical sterilization in female cats (Vandsandt et al., 2023) and dogs thanks to the support of the Michelson Found Animals Foundation. We hope our work in the development of contraceptive for use in companion animals will contribute to promote animal welfare and reduce feral animal overpopulation.
In humans, contraceptives that inhibit early follicle development rather than ovulation, as current oral contraceptives do, could have many unexplored advantages, such as fewer side effects, lack of menses, and potentially delayed ovarian aging. Based on these properties we have active projects to develop novel contraceptive molecules targeting AMHR2 which we hope could empower women’s reproductive choices in the developing world, thanks to the support of the Bill and Melinda Gates Foundation.
Female domestic cats involved in the study of the viral-vectored delivery of a feline AMH transgene as a contraceptive strategy.
Oocyte counting by organ clarification to evaluate the ovarian-suppressive effect of AMH.
Expression of murine AMHR2 (green) in granulosa cells of all follicle types.
Oncofertility and aging
Women are born with a set number of eggs, representing their “ovarian reserve” which is used throughout their life and depleted at menopause. As the ovarian reserve declines, either because of toxic chemotherapy, genetic predispositions, or natural aging, the hormones produced by the ovary decrease, which negatively affects many aspects of health including bone loss, cardiovascular diseases, reproductive disorders, and problems with sleep amongst others. Developing methods to slow down the depletion of ovarian reserve could be highly beneficial for women’s health. Maintenance of ovarian reserve as we have demonstrated with AMH treatment in mouse models of chemotherapy (Kano et al., 2017), could have broad applications in the clinic, from preserving fertility and hormonal health in aging women to delaying ovarian insufficiency in genetically susceptible women or patients undergoing chemotherapy. Our laboratory aims to understand how chemotherapy damages the ovary and uterus, and how we may help preserve fertility and hormonal health in women cancer survivors in an NICHD sponsored study.
Reproductive development and infertility
Controlling early follicle development with AMH also has unexpected applications in the treatment of infertility. We have found that pre-treatment with AMH can help recruit a large wave of synchronized follicles and increase the success of ovarian stimulation for IVF (Kano et al., 2019). The laboratory is exploring the role of AMH in all aspects of follicular development with the goal of improving the care of Reproductive Endocrinology and Infertility patients.
Furthermore, uterine-factor infertility has long been a black box in reproduction. While we have a good understanding of factors affecting ovulation and gamete health, the uterine causes of implantation failure, fetal loss, and pre-term labor remain poorly understood. We have identified a novel progenitor cell in the developing uterus, present in mice, rats, and humans, which when dysregulated can lead to severe uterine hypoplasia and infertility later in life (Saatcioglu et al., 2019). Understanding how the uterus develops may be key to explain different disorders of Müllerian development, ranging from Müllerian agenesis to uterine malformations, and uterine hypoplasia.
Uterine hypoplasia (right) following chemotherapy compared to control (left).
Ovarian cancer
Ovarian cancer is an insidious disease with 70% recurrence, an almost universal death knell even after effective debulking intraperitoneal surgery and apparent complete response to chemotherapy. Approximately 15,000 women die from ovarian cancer every year in the US. The focus of the laboratory for the past few years has been to apply new emerging technologies to the treatment of this disease, from gene therapy delivery of inhibitory hormones (Pepin et al 2015), to in vivo CRISPR-Cas9 gene editing of patient-specific cancer susceptibilities, and the development of novel immunotherapies thanks to studies sponsored by the Department of Defense, the Ovarian Cancer Research Alliance, and the Koch Institute.
Using novel mouse models of ovarian cancer developed in collaboration with Robert Weinberg at the Whitehead Institute, we have identified mechanisms of resistance to currently available immunotherapies, which have had limited success in ovarian cancer. In particular, we have recently identified follistatin (FST) as a novel immunotherapy target which when inhibited can solicit complete responses to immune checkpoint therapy in ovarian cancer (Iyer et al., 2020).
The publication of new syngeneic mouse models of ovarian cancer and the identification of FST as a new immune checkpoint resistance target.